Insulin is a peptide secreted by pancreatic beta cells, and plays a central role in the control of blood glucose in the body. If the amount of insulin secreted is lacking or the secreted insulin does not function properly in the body, the blood glucose level will be elevated, causing metabolic disease called diabetes. When the insulin is not secreted properly or does not function properly in the body, the blood glucose level is increased without regulation, and this type of diabetes is called type II diabetes. Type I diabetes is caused when the pancreas does not make enough insulin to regulate the increase of blood glucose. Type II diabetes is usually treated by administering oral hypoglycemic agents which mainly consist of chemical compounds, and sometimes insulin may be administered to some of the patients. On the other hand, for treating type I diabetes, administration of insulin is essential.
The widely-used insulin treatment is an injection of insulin before and after meals. Insulin is currently available in a formulation for parenteral injection and administered subcutaneously in principle, and depending on the duration of treatment, a method of administration is different. Administration of insulin by injection is more effective in reducing blood glucose level compared to the oral medicine, and it can be safely applied in the circumstances when an oral drug cannot be used. Also, parenteral injection of insulin does not have a limitation of dose, however since it has to be continuously administered three times a day, it has disadvantages such as causing an aversion to needles, difficult administration method, symptoms of hypoglycemia, and symptoms of weight gain due to prolonged insulin administration. Especially, the weight gain increases a risk of developing cardiovascular diseases and may disrupt the regulatory function of body for blood glucose level. Meanwhile, there have been many attempts to maximize the therapeutic effect of an insulin peptide drug by maintaining a high drug level in blood for a long period of time, after administering the drug into the body. As a result, long-acting insulin has been developed, manufactured, and commercialized. Examples of such long-acting drug include Lantus (insulin glargine; Sanofi Aventis) and Levemir (insulin detemir; Novo Nordisk). Unlike neutral protamine Hagedorn (NPH) insulin, the long-acting drugs have a lower risk of hypoglycemia during hypnoidal state. In particular, Levemir alleviates the symptom of weight gain. However, the administration method involving one or two injections per day is still remained as a disadvantage.
Meanwhile, a glucagon-like-peptide-1 (GLP-1), which is a type of insulinotropic peptide, is an incretin hormone secreted from L-cell of ileum and large intestine. The main function of GLP-1 is to increase the secretion of insulin for establishing a glucose-dependent insulin secretion in the body, thereby preventing hypoglycemia. With this effect, GLP-1 can be applied to treat type 2 diabetes. However as the serum half-life of GLP-1 is as short as 2 minutes, it has high limitation to be developed into a drug. Accordingly, a new GLP-1 agonist called exendin-4 has been developed and manufactured. Exendin-4 is a GLP-1 agonist produced in the salivary gland of Glia monster lizard. Furthermore, exendin-4 is resistant to dipeptidyl peptidase-4 (DPP-IV) and has a higher physiological activity than GLP-1. Thus, exendin-4 has 2 to 4 hour-long half-life in the body, which is a lot longer than that of GLP-1 (U.S. Pat. No. 5,424,286). However, a sufficient duration of physiological activity of drug cannot be achieved merely by increasing resistance to DPPIV. For instance, the currently available exendin-4 (exenatide) has to be administered twice a day to the patient by injection, and it still has disadvantages of causing vomiting and nausea.
Therefore, as a method to maintain the activity of protein drug and improve the stability thereof in the body simultaneously for resolving the above problems, the present inventors have previously suggested a development of long-acting protein conjugate by linking a known physiologically active polypeptide and immunoglobulin Fc region through covalent bonding by using a non-peptidyl polymer as a linker (Korean Patent Registration No. 10-0725315). In particular, it was previously confirmed that each of long-acting insulin conjugate and long-acting exendin-4 conjugate has remarkably increased in vivo durability (Korean Patent Registration No. 10-1058290 and Publication No. 10-2011-0134210). However, if a therapeutically effective amount of insulin or exendin-4 is administered for maintaining a stable blood glucose level; this may cause weight gain or symptoms of vomiting and nausea. Therefore, there is a high demand for developing a therapeutic method that can reduce a dosage of drug and frequency while providing excellent therapeutic effect for diabetes.